Formulations of terlipressin

a technology of terlipressin and terlipressin, which is applied in the field of formulations of terlipressin, can solve the problems of side effects in up to 40% of patients

Pending Publication Date: 2022-07-28
BIOVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, terlipressin can cause side effects in up to 40% of patients.

Method used

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  • Formulations of terlipressin
  • Formulations of terlipressin
  • Formulations of terlipressin

Examples

Experimental program
Comparison scheme
Effect test

example 1

Acid Formulations

[0093]Terlipressin acetate formulations containing aspartic acid (with and without nitrogen) at a pH of 4.5 are prepared.

[0094]With Nitrogen Protection: Perform all procedures using N2 protection. Sparge water for injection (WFI) prior to addition of materials. Overlay N2 during mix operations, discontinuing only to add solid materials. Keep solution at 20-25° C.

[0095]Add WFI to formulation vessel, equivalent to 80% of the final QS volume.

[0096]Add aspartic acid to WFI; rinse aspartic acid weighing vessel with WFI (rinse volume< / =to 3% of final volume). Mix to dissolve

[0097]Adjust pH to 4.0 with 0.1 N NaOH solution.

[0098]Add terlipressin acetate with WFI rinses (rinse volume< / =5% of QS volume). Mix to dissolve.

[0099]Adjust pH to 4.5 with either 0.1 N NaOH or 0.1 N acetic acid solution (expect the pH to be 4.6 after addition of terlipressin acetate to pH 4.0 solution).

[0100]Bring to final volume with low 02 WFI. Readjust pH if required.

[0101]Without Nitrogen Protecti...

example 2

id Formulations

[0109]Terlipressin acetate formulations containing acetic acid (with and without nitrogen) at a pH of 4.5 are prepared.

[0110]With Nitrogen Protection: Perform all procedures using N2 protection. Sparge WFI prior to addition of materials. Overlay N2 during mix operations, discontinuing only to add solid materials. Keep solution at 20-25° C.

[0111]Add WFI to formulation vessel, equivalent to 80% of the final QS volume.

[0112]Add acetic acid to WFI; rinse ascetic acid weighing vessel with WFI (rinse volume< / =to 3% of final volume). Mix to dissolve

[0113]Adjust pH to 4.0 with 0.1 N NaOH solution.

[0114]Add terlipressin acetate with WFI rinses (rinse volume< / =5% of QS volume). Mix to dissolve.

[0115]Adjust pH to 4.5 with either 0.1 N NaOH or 0.1 N acetic acid solution (expect the pH to be 4.6 after addition of terlipressin acetate to pH 4.0 solution).

[0116]Bring to final volume with low 02 WFI. Readjust pH if required.

[0117]Without Nitrogen Protection: Keep solution at 20-25° C...

example 3

of Terlipressin Formulations

[0125]The impact of aspartic acid formulations with and without nitrogen at pH 4.5 and acetic acid formulations with and without nitrogen at pH 4.5 were assessed at 2° C.-8° C., 25° C. and 40° C. at 3 months and 4 months. The aspartic acid and acetic acid formulations were prepared by methods similar to those described in Examples 1 and 2. The results shown in Tables 6-9 below are shown in terms of % label strength (LS) for the active ingredient (terlipressin acetate), as well as the % change as compared to the day 0 (initial) time point. Table 10 shows a comparison of the % LS data presented in Tables 6-9. Percent label strength was calculated using the following formula: (mg / mL found) / (1.0 mg / mL label strength)×100%.

TABLE 6Aspartic Acid Formulation at pH 4.5 Stability2° C.-8° C.25° C.40° C.Time%%%%%%(months)LSchangeLSchangeLSchange096.95—96.95—96.95—396.53−0.4295.87−1.0894.00−2.95498.341.3997.380.4394.30−2.65

TABLE 7Aspartic Acid Formulation with Nitroge...

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Abstract

The disclosure provides pharmaceutical compositions comprising terlipressin having increased concentration with long term storage stability.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application Ser. No. 62 / 851,366, filed May 22, 2019, the contents of which is hereby incorporated by reference in its entirety.BACKGROUNDField[0002]The disclosure is directed to stable pharmaceutical compositions of terlipressin having increased concentrations at room or ambient temperature or under refrigeration.Technical Background[0003]Terlipressin is a synthetic vasopressin that is approved in many countries outside of the United States to treat the life-threatening complications of cirrhosis, including hepatorenal syndrome (HRS) and esophageal bleeding (EVB). Its use is limited to the hospital setting due to its short half-life (Nilsson, et al., (1990) Drugs Explt Clin. Res., XVI(6):307-314), necessitating its administration as an intravenous bolus usually every 4 to 6 hours. Additionally, terlipressin can cause side effects in up to 40% of patients. Severe side effects—incl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/12A61K47/18A61K9/00A61K47/02A61K47/12
CPCA61K38/12A61K47/183A61M5/178A61K47/02A61K47/12A61K9/0019A61K9/08A61K38/095A61K47/26A61K47/20A61K38/2278A61M5/002A61M5/14248
Inventor MARKHAM, PENELOPEADAMS, JONATHANSMITH, DENISEBACARDIT CABADO, JORGE
Owner BIOVIE INC
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